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S2 Case 3 - asthma & COPD > Case Study: Salbutamol/Salmeterol > Flashcards

Case Study: Salbutamol/Salmeterol Flashcards

1
Q

What is asthma?

A

Chronic inflammatory disorder of airways in response to external stimuli

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2
Q

What are patients with asthma characterised by?

A

Inflammation
Bronchospasm

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3
Q

What causes bronchodilation?

A

Adrenergic system

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4
Q

What causes bronchoconstriction?

A

Cholinergic system

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5
Q

What is used to treat bronchospasm?

A

Salbutamol
(Adrenergic agonist)
RELIEVER

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6
Q

What is used to treat inflammation?

A

Corticosteroid
eg. beclomethasone

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7
Q

Describe brief process of inflammation

A

Antigen + Ab (IgE)
A-A complex
Bronchoconstriction mediators
= histamine, leukotrienes + prostaglandins

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8
Q

Describe 1st part of asthma drug history

A

Adrenaline
BUT cardiac effects
Agents similar to adrenaline structure
Isoprenaline = NO cardiac effects BUT short acting

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9
Q

Describe 2nd part of asthma drug history

A

Adrenoreceptors
Alpha + beta

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10
Q

What were alpha adrenoreceptors defined as?

A

Sensitive to adrenaline + insensitive to isoprenaline

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11
Q

What were beta adrenoreceptors defined as?

A

Sensitive to isoprenaline + least sensitive to noradrenaline

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12
Q

Describe the 3rd part of asthma drug history

A

Beta 1 receptors
Beta 2 receptors

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13
Q

Where are beta 1 receptors found?

A

Heart

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14
Q

Where are beta 2 receptors found?

A

Bronchial smooth muscle

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15
Q

Describe the chemistry of noradrenaline + adrenaline

A

Very similar structure
Both acidic + basic groups
Physiologically behave as a base
= 90% protonated at pH 7.4

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16
Q

Where is noradrenaline synthesised?

A

In neuron in CNS + autonomic nervous system

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17
Q

Where is noradrenaline + adrenaline derived from?

A

L-tyrosine by series of enzyme catalysed reactions

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18
Q

What is the aim of metabolism?

A

To change drugs so they have groups that make them more H2O soluble

19
Q

What type of receptors are adrenergic receptors?

A

G protein-coupled receptor

20
Q

How do adrenergic receptors affect biological activity?

A

Release secondary messenger molecules inside the cell after the bind an extracellular agonist

21
Q

How do noradrenaline bind?

A

Ionic bond
H bonds
Van der Waals

22
Q

What can noradrenaline interact with?

A

Alpha/ beta

23
Q

What can adrenaline interact with?

A

Alpha/ beta

24
Q

What does isoprenaline interact with?

A

Selectively beta

25
Q

What did the new drug need to be?

A

STABLE
More selective for beta 2

26
Q

What did they first decide about the new formula?

A

Substituent had to be in meta position

27
Q

What was decided in round 2 of synthesis?

A

Tert-butyl derivative added
= did increase some activity

28
Q

What was decided in round 3 of synthesis?

A

Methyl OH was added in meta position

29
Q

What did the tert-butyl group prevent?

A

CYP450 metabolism

30
Q

What was the only problem with salbutamol now?
(New formulation)

A

Chiral compound
= enantiomers one more active

31
Q

How do you separate enantiomers?

A

One will be insoluble to what the other will be soluble in

32
Q

Which enantiomer was more active of salbutamol?

A

R isomer

33
Q

What do substituents on amine groups determine?

A

Alpha or beta selectivity

34
Q

What do substituents on alpha C show?

A

An increased duration of action

35
Q

What needs to be substituted for an adrenergic agonist to demonstrate beta 2 selectivity?

A

Substituted ring:
Phenolic hydroxy in para
Substituent in meta for H bonding
NEEDS to be resistant to COMT metabolism

36
Q

How long does salbutamol last?

A

4-6hrs
BUT is a reliver

37
Q

What is salbutamol inadequate for?

A

Nocturnal bronchospasm

38
Q

For a long-acting beta 2 agonist what 2 major sites of interaction must it have?

A

Active site
Hydrophobic domain for anchoring

39
Q

What were the 2 main observations from the LABA investigation?

A

To maintain potency 5-6 Cs
To obtain long duration logP = 3.3 - 4.5

40
Q

What is the importance of O in LABA investigation?

A

O placed close to N
O placed close to phenyl ring

41
Q

Describe the binding of Salmeterol

A

Reversible
Can be repeated several times

42
Q

What problem was suggested about salmeterol?

A

Persists in tissues
BUT interact freely + reversibly

43
Q

What was the original concept of salmeterol exo-site?

A

Long chain interacts with non-polar region in cell membrane
“Exo-site” within vicinity of beta receptor

S2 Case 3 - asthma & COPD (25 decks)

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